Parkinson-dementia complex (PDC) of the Chamorros on Guam and surrounding Mariana Islands is a unique neurodegenerative disease that remains a significant public health burden to the older members of this indigenous ethnic minority. Current data indicate that PDC is a complex phenotype that likely derives significant contributions from advancing age, inherited susceptibilities, and as yet to be clarified environmental factors. This complex phenotype represents a severe challenge to standard genomic and epidemiologic approaches to identifying key pathogenic elements in PDC. Identification of detergent-insoluble (DI) protein has provided keen insight into the molecular pathogenesis of other complex neurodegenerative diseases like Alzheimer's disease. Here we will test the hypothesis that discovering and quantifying DI proteins specific to PDC will provide much needed new perspective on this enigmatic disease and perhaps other neurodegenerative diseases. We will test our hypothesis through specific aims that employ novel discovery tools focused at the protein level so as to have the capacity to capture pathologic changes from either genetic or environmental influences. We will: (i) discover and quantify relative amounts of DI protein specific to PDC using LC-MALDI-TOF-TOF with isobaric tagging for relative and absolute protein quantification, (ii) confirm and validate results using a series of antibody-based techniques, and (iii) localize validated proteins in tissue sections from patients with PDC, other tauopathies, and appropriate controls. Once complete, data from these experiments will provide a fresh and unique perspective on new elements in the pathogenesis of PDC and thereby serve to focus future genetic screens, searches for environmental influences, and evaluation of experimental therapeutics in model systems. [unreadable] [unreadable] [unreadable]